Alzheimer’s Disease and Protein Misfolding | Role of Amyloid and Tau
Learn about importance of protein folding, Chaperons, and how protein misfolding contributes to Alzheimer’s disease, focusing on amyloid-β plaques, tau tangles, and their impact on neuronal degeneration.
Protein
In animals, proteins are the most abundant macronutrient. Protein plays an important role in biological systems such as metabolic reactions, cell signalling, structural support, enzymes, hormones, apoptosis etc.
Protein consists of a polypeptide that consists of a long chain of amino acids. In a polypeptide chain, amino acids are connected to each other with peptide bond.
Protein structure and folding
At the structural level, proteins are classified into four structures: Primary, secondary, tertiary, and quaternary structures. Each type of protein has a specific protein sequence and protein structure. Amino acids are arranged in a three-dimensional structure to form a protein, which is more stable and active.
Protein folding
Protein folding is a physical process that is synthesised by the ribosome that changes an amino acid sequence into a more ordered and stable three-dimensional structure.
The concept of protein folding is that the amino acid sequence contains all the essential information for proper folding and conversion of the amino acid into the correct three-dimensional structure. Therefore, it was believed that it is spontaneous and self-assembles without any cellular factors.
Primary Structure of Proteins
The primary structure is the simplest structure of a protein. In primary structure, amino acids are bound to each other in a specific manner to form a polypeptide chain. These amino acids are attached through covalent peptide bonds. A covalent peptide bond is formed when the amino terminal (N-terminal) of one amino acid is attached to the carboxy terminal (C-terminal) of another amino acid. In a polypeptide chain, based on the nature of the free group, one end is known as the C-terminus and the other end is known as the N-terminus.
The factor that determines protein folding is the specific order of the amino acid sequence rather than the composition of amino acids. During folding, these different parts of the protein sequence interact with each other to form bonds.
Secondary Structure of Proteins
The secondary structure of a protein is formed by the folding of a polypeptide chain by hydrogen bonds that make the protein more stable. Hydrogen bonding is formed between the amino acid and the carboxy group in the polypeptide chain. These hydrogen bonds could be intramolecular or intermolecular hydrogen bonding. Secondary structure formation is the first step of the protein folding process.
The common types of secondary structure of protein are the α-helix and β-pleated sheets.
Alpha (α)-helix:
An α-helix is formed when the –NH group of an amino acid forms a hydrogen bond with the –CO group of an amino acid in a polypeptide chain. The polypeptide chain coils into a right-handed spiral due to regular and repeated hydrogen bonding that makes the α-helix strong and stable.
Beta(β) -pleated sheet:
In a β-pleated sheet, hydrogen bonds are formed between adjacent polypeptide chains or different segments of the same chain of polypeptides. In a β-pleated sheet, hydrogen bonds are formed between the carbonyl group (-CO) of one amino acid of one polypeptide chain and the amide hydrogen (-NH) group of an amino acid on another polypeptide chain.
Tertiary structure of protein
In the tertiary structure of a protein, α-helix and β-pleated sheets fold to form a globular structure. In tertiary structure, polypeptide chains (single protein molecules) fold into unique three-dimensional structures that make the structure more compact and stable. Polypeptide chain folding occurs due to the interaction between the R groups of amino acids. Tertiary structure is compact and contains one or more than two domains.
The bond between the R groups of amino acids is a hydrogen bond, hydrophobic bond, hydrostatic bond, disulfide bond, or ionic bond that makes the tertiary structure compact and stable.
The α-helix and β-pleated sheet are both hydrophilic and hydrophobic, also known as amphipathic in nature. This amphipathic nature of α-helix and β-pleated forms a tertiary structure of protein where hydrophilic sides are facing the aqueous environment and hydrophobic sides are facing towards the hydrophobic core of the protein. After the formation and stabilization of the tertiary structure of a protein, it is stabilized by hydrophobic interactions and covalent bonds (disulfide bridges formed between cysteine residues).
Quaternary structure of protein
In the quaternary structure of a protein, different tertiary structure proteins spatially arrange to form a three-dimensional quaternary structure. In this structure, two or more polypeptide chains are linked and form a functional unit known as a subunit. These subunits spatially arrange and form a quaternary structure.
In quaternary structure, hydrostatic bonds, hydrogen bonds, covalent bonds, disulfide bonds, and ionic bonds hold the subunits, stabilize them, and make strong, three-dimensional, large protein complexes.
These protein complexes are in the form of multimers when two or more polypeptide chains are included. Quaternary structure is called “dimers” when two subunits or polypeptide chains and “trimers” when three polypeptide chains unite to form a complex.
Quaternary structure is called homodimers when identical polypeptide chains (subunits) unite and heterodimers when different polypeptide chains unite.
Protein folding depends on the specific order of the amino acid sequence, which folds into a unique three-dimensional structure to create a biologically active tertiary structure. Some parts of the protein chain have their specific three-dimensional fold that determines a specific function; these are called “domains.” These domains play an important role in evolution, as they specify protein function and can be conserved. Sometimes, domain sequences duplicate or rearrange during evolution, which can create new proteins, give proteins new functions, or make them non-functional.
Molecular Chaperone proteins in protein folding
Chaperons are a group of heat shock proteins (Hsp). They have significant function in protein folding, protein assembly or disassembly, and their translocation. The heat-shock proteins (Hsp) are highly conserved in prokaryotes and eukaryotes. They protect the protein and stabilize the protein structure that has been partially denatured due to increased temperature.
The most abundant chaperons that are responsible for the selection of precursor protein to the plastid translocation machinery are Hsp90 and Hsp70. Both Hsp90 and Hsp70 work with Hsp93, Cpn60, and other molecular Chaperons that cause transfer of preprotein into plastids, mature protein folding and assembly, and intraorganellar localization.
Molecular chaperon’s main function is to regulate and prevent the protein from misfolding and ensure correct folding. This is the reason why some of the chaperon’s protein are classified as heat shock protein. Molecular chaperons do not involve in the final structure of a protein, but they assist the protein folding and convert it into a stable three-dimensional structure. Chaperons make sure that proteins fold properly while the polypeptide is being synthesized by the ribosome.
Chaperons do not provide additional information for protein folding. The amino acid sequence solely helps in protein folding confirmation. Instead, chaperones catalyse the protein folding process by assisting the self-assembly process and conversion into a stable protein structure. Chaperons help in protein folding by binding to polypeptides and correct the unfolded or partially unfolded polypeptide chain and convert them into correct, stable and active three-dimensional protein structure.
In case if there are no chaperons, unfolded or partially folded polypeptide chains are unstable and inactive and more prone to misfolding or aggregate into insoluble protein complex. Though protein folding is a self-assembly process, molecular chaperons regulate and prevent incorrect protein folding, misfolding and aggregation, allowing the polypeptide chain to achieve its more stable three-dimensional protein structure.
Importance of Protein structure and protein folding
Protein folding and protein structure is essential for the stability and functionality of proteins. Under physiological conditions, protein folding creates active proteins that maintain the health of the brain and body.
Protein folding starts while the polypeptide chain is co-translationally associated with the ribosome.
Due to genetic factors, mutations, ageing, or stress factors, the protein is unable to fold properly, and instead it starts misfolding.
Protein misfolding
There are some factors which influence the folding of proteins, leading to the generation of inactive or non-functional proteins. In some cases, improper or misfolding of protein can cause toxicity to health. The cellular environment where protein is synthesized highly influences the functionality of protein folding.
Protein misfolding disturbs the structure of protein, which leads to loss of function, or toxic gain of function. These misfolded proteins polymerize improperly and form fibrils, ribbons or aggregates.
Under stress conditions, proteins expose hydrophobic regions which are hidden in native confirmation. These hydrophobic exposures lead to instability and aggregation. Accumulation of unstable, inactive aggregate proteins causes different types of neurodegenerative diseases. Aggregate proteins are highly neurotoxic and affect various biological functions such as synaptic activity.
Somatic gene sequence mutations affect the protein folding and make protein unstable. Error in transcription and translation mechanism cause altered folding that leads to protein misfolding or abnormal protein.
In neurons, misfolded proteins deposit into insoluble aggregates, which further cause various effects such as synaptic dysfunction, mitochondrial impairment, and neuroinflammation.
Alzheimer disease
Alzheimer’s disease is a neurological disorder, affects millions of people worldwide. It affects people of age 60 or above and cause dementia.
In Alzheimer disease associated with aging that cause dementia, in which their gradual degradation of brain neurons that result memory impairment.
In Alzheimer disease, there are two types of protein that deposit, Amyloid plaques and Neurofibrillary tangles. Amyloid plaques consist of 40- to 42-residue peptide known as β-amyloid protein(Aβ). Amyloid plaques are deposited in brain parenchyma and around the cerebral vessel walls, whereas Neurofibrillary tangles are composed of aggregates of hyperphosphorylated tau protein and present in the cytoplasm of degenerating neurons.
Reason behind Alzheimer disease is protein misfolding, protein unable to fold properly that leads to accumulation of amyloid- β plaques outside of cell and formation of tau neurofibrillary tangles in the cortical area and middle temporal of neurons.
Molecular mechanisms behind protein misfolding
In Alzheimer’s disease, amyloid precursor protein (APP) responsible for the accumulation of amyloid- β plaques.
In healthy person, enzyme cleaved the APP without causing any damage, but in case of Alzheimer patient, APP follow another pathway in which β- and γ-secretases cleaves APP that further leads to accumulation of plaques.
Amyloid-β (Aβ) is a soluble peptide that produces after the cleavage of APP. β-secretase forms the N-terminal end of Aβ, while γ-secretase forms the C-terminal end results in production of amyloid-β fragments, especially Aβ42. Aβ42 structure is such a way that they aggregate together form clumps, results in formation of toxic oligomers.
These toxic oligomers also known as “seed particle” and when these seed particle enter into neuronal cell membranes, they disrupt the calcium channel. These seed particle or aggregated amyloid-β fragments formed a pore like structure that allow calcium ions to enter the cell. Excess calcium ion imbalance the neurons and disrupt the synaptic plasticity of neurons, which is essential for learning and memory.
When amyloid-β oligomers bind to NMDA receptors on the neuron surface, they over activate these NMDA receptors, leads to more calcium to enter the cell. Overtime amyloid-β oligomers clumps together to form larger amyloid fibrils and plaques. Accumulation of plaque induce immune cell such as microglia and astrocytes that secret inflammatory cytokines. Inflammatory cytokines start damaging nearby neurons.
In Alzheimer disease, tau protein hyperphosphorylated and make microtubules less stable. Due to this tau protein detach from microtubule and assemble into twisted structure known as paired helical filaments (PHFs). In neuron, PHFs further aggregate to form neurofibrillary tangles (NFTs) and disturb the neuron structure, impair nutrient transport system and waste removal. Hyperphosphorylated tau also have ability to spread from one neuron to another, stimulate misfolding of protein.
Spread of Hyperphosphorylated tau protein from one neuron to another neuron make Alzheimer disease more aggressive across different brain regions and worsen the symptoms of patients.
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References:
- Sharma, A., Srivastava, S., Gupta, P., Sridhar, S.B., Tariq, M., Rao, G.K., Kumar, S. and Malik, T., 2025. Targeting protein misfolding in Alzheimer’s disease: The emerging role of molecular chaperones. Biomedicine & Pharmacotherapy, 191, p.118531.
- Soto, C. and Estrada, L.D., 2008. Protein misfolding and neurodegeneration. Archives of neurology, 65(2), pp.184-189.
- Reynaud, E., 2010. Protein misfolding and degenerative diseases. Nature Education, 3(9), p.28.
